Decoding Breast Cancer Drug Resistance

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Scientists have identified a new potential target for addressing drug resistance in breast cancer and potentially other tumor types. In vitro and in vivo studies by a team at the U.S. Department of Energy’s Lawrence Berkeley National Laboratory have found that a gene known as FAM83A has oncogenic properties, and when overexpressed in cancer cells confers resistance to EGFR-tyrosine kinase inhibitor (EGFR-TKI) drugs and also promotes tumor proliferation and invasion.

Mina Bissell, Ph.D., and colleagues, hypothesized that resistance to EGFR-TKIs may occur in part as a result of a molecular mechanism that triggers phosphorylation signaling downstream of EGFRs, so to probe this further they developed a novel three-dimensional cell culture assay based on the phenotypic reversion of malignant cells into phenotypically nonmalignant cells, to screen for genes involved in EGFR-TKI resistance both in normal and cancerous human cell lines. The results showed that while noncancerous human breast tissue doesn’t express FAM38A, the protein was produced at high levels in every breast cancer cell line examined, and was particularly elevated in cell lines that were most resistant to EGFR-TKIs. Further analyses confirmed that FAM38A interacts with and triggers phosphorylation of signaling proteins downstream of EGFR, that act to block the therapeutic effects of EGFR-TKIs.

While more research is needed to further unpick the function of FAM83A and related proteins, the published data highlights the potential importance of this family of proteins as potential drug targets, and helps explain existing data demonstrating a clinical correlation between high FAM83A expression and poor cancer prognosis. “The beauty of this study is that it not only helps explain why some breast cancer patients are resistant to EGFR-TKIs, but it also reveals a whole new family of potential oncogenes that could be a target for all types of cancer, including breast cancer,” Dr. Bissell states.

The work also validates use of the 3D phenotypic reversion technology, which was originally developed at the Berkeley laboratory. “Our 3D phenotypic reversion assay revealed the malignant phenotype, something that could not have been done with a 2D assay,” she adds. “This is the first time we have used our assay to discover a potential target for cancer drugs, but it shows that an assay like ours can be a powerful tool for finding new targets and therapies.”

Dr. Bissell et al report their data in the Journal of Clinical Investigation, in a paper titled “FAM83A confers EGFR-TKI resistance in breast cancer cells and in mice.”